JP2002510681A - N-aryloxyethyl-indolyl-alkylamines for treating depression - Google Patents

Abstract

Compounds effective in treating disorders of the serotonin-affected neurological systems are provided, such compounds having formula (I), wherein: R1 is hydrogen, lower alkyl, phenyl, or substituted phenyl; X and Y together complete a lactam, imidazole, imidazolone, or thioimidazolone ring; Z is hydrogen, halogen, or lower alkoxy; W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or a trifluoromethyl group; and n=2 to 5; or pharmaceutically acceptable salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to compounds useful for treating diseases (eg, depression and anxiety) affected by disorders of the nervous system affected by serotonin. More particularly, the present invention relates to various N-aryloxyethyl-indolyl-alkylamines useful for treating such diseases.

BACKGROUND OF THE INVENTION Pharmaceutical compounds that enhance serotonin (5-HT) transmission are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective drugs that affect serotonin act through a variety of physiology, which indicates that such drugs may have a number of undesirable side effects (eg, blurred vision, Dry and sedated). A recently introduced compound, a selective serotonin reuptake inhibitor (SSRI), inhibits the active removal of 5-HT released at the synapse from the synaptic cleft via the presynaptic serotonin transporter. By doing so, it works dominantly. This 5-HT blockade mechanism cannot fully explain their therapeutic activity, as SSRIs require several weeks to exert their full therapeutic effect. This 2-week induction, which occurs before a sufficient antidepressant effect is observed, is presumed to be due to the involvement of the 5-HT _1A autoreceptor, which suppresses the excitatory activity of 5-HT neurons, causing a diminished therapeutic effect. Studies suggest that 5-HT autoreceptor desensitization occurs several weeks after SSRI administration, resulting in a sufficient antidepressant effect in most patients. Therefore, Oshikire this negative feedback by using 5-HT _{1 A} antagonist, is believed to accelerate increase the antidepressant response clinical. According to a recent study by Artigas et al. [ Trends Neurosci. , 19: 378-383 (1996)], 5-HT _1A activity and 5-HT uptake in a single molecule. In combination with the inhibition, an antidepressant effect that acts more strongly and quickly can be achieved.

[0003] For example, US Pat. No. 3,371,098 discloses sec- and tert-indolylethylamines useful as sedatives, anticonvulsants and analgesics.

[0004] US Pat. No. 5,436,264 discloses N-aryloxyalkyl-tryptamine-like compounds of the following formula as α-1-adrenergic receptor antagonists for the treatment of cardiovascular disorders: .

[0005]

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[0006] EP 0722 941 A2 discloses a series of hetero-oxyalkaneamines of the following formula for the treatment of depression and other conditions where serotonin uptake inhibitors are used. Preparations are disclosed.

[0007]

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[0008] Japanese Patent Nos. 05255302 and 09040648 disclose diseases related to the central nervous system.
The following compounds useful in the treatment of (eg, anxiety and depression) are disclosed.

[0009]

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DISCLOSURE OF THE INVENTION [0010] The present invention relates to a novel class of molecules capable of acting simultaneously with the 5-HT transporter at the 5-HT _1A autoreceptor. Such compounds are therefore
It may be useful in treating depression and other serotonin disorders.

The compounds of the present invention have the formula I:

[0012]

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Wherein R ₁ is hydrogen, lower alkyl, phenyl or substituted phenyl; X and Y together form a lactam, imidazole, imidazolone or thioimidazolone ring; Z is hydrogen, W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl group; and n = 2 to 5], N-aryloxyethyl-indolyl-alkylamine or a drug thereof. Is an acceptable salt.

The compounds of the present invention preferably have the formula I wherein R ₁ is hydrogen; X and Y together form an imidazole or thioimidazolone ring; Z is halogen or hydrogen; W is halogen or hydrogen; and a compound represented by n = 2 to 3] or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are more preferably selected from the following compounds: [2- (3H-benzimidazol-4-yloxy) -ethyl]-[3- (1H-indol-3-yl) 4- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1,3-dihydrobenzimidazol-2-one; 4- {2- [3 -(1H-Indol-3-yl) -propylamino] -ethoxy} -1,3-dihydrobenzimidazol-2-thione; [2- (3H-benzimidazol-4-yloxy) -ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl] -amine; [2- (6-chloro-1H-benzimidazol-4-yloxy) -ethyl]-[3- (5-
Fluoro-1H-indol-3-yl) -propyl] -amine; and 7-fluoro-4- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1,3 -Dihydro-indol-2-one.

As used herein, the terms “lower alkyl” and “lower alkoxy” are meant to include straight and branched carbon chains having 1-6 carbon atoms. The term "halogen" is meant to include fluorine, chlorine, bromine and iodine. "Substituted phenyl" may include substitution by halogen, lower alkyl, lower alkoxy and cyano groups.

The compounds of formula I may be used advantageously in the form of pharmaceutically acceptable acid addition salts having the utility of a free base. Such salts can be prepared by methods known to those skilled in the art, but are formed using either inorganic or organic acids. Such inorganic and organic acids include, for example, fumaric acid, maleic acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid , Salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid,
Stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid.

The compounds of the present invention may be prepared by any suitable method known to those skilled in the art.
However, these compounds may be advantageously prepared according to any one of the schemes 1-4 below. In these schemes, the intermediate compounds exemplified below are identified in parentheses. The compounds made in each of Schemes 1-4 have been identified by reference to the appropriate examples. However, it should be understood that each of Schemes 1-4 is applicable to a genus compound of Formula I.

[0019]

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[0020]

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[0021]

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[0022]

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The present invention will now be described in more detail by the following specific but non-limiting examples.

Intermediate 1 3-Indolyl-propionamide 3-indolepropionic acid (150 mL) in anhydrous tetrahydrofuran (150 mL)
15 g, 79 mmol) and 1,1'-carbonyldiimidazole (16.7 g, 1
(00 mmol) was stirred at room temperature for 1.5 hours. The solution was then blown with NH ₃ for 2.5 hours at room temperature. The solvent was removed under vacuum and the residue was ethyl acetate (500 mL
). The organic solution was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. The white solid was collected and dried under vacuum. 10.42 g (96%); mp 124-125 [deg.] C; MS EI m / e 188 (M ^<+> ).

Intermediate 2 3-Indolyl-propylamine To a solution of 3-indolyl-propionamide (5 g, 24.7 mmol) in anhydrous tetrahydrofuran (150 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 100 mL) was added slowly. After refluxing the reaction mixture for 3 hours, it was quenched at 0 ° C. with water (4 mL), 15% sodium hydroxide (4 mL) and water (12 mL) sequentially. The mixture was filtered through celite and concentrated under vacuum. Chromatography (10% methanol-methylene chloride + aqueous ammonia) gave 4.0 g (86%) of the product as a white solid. Melting point 58-60.5
° C; MS EI m / e 174 (M ^{* +} ).

Intermediate 3 2- (2-chloro-ethoxy) -6-nitro-phenylamine 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260. A slurry containing 0 g (2.65 mol), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (750 mL) was refluxed for 24 hours. The mixture was cooled, filtered and the solid was washed with ethyl acetate. The filtrate was concentrated to an oily residue, which was dissolved in ethyl acetate (500 mL). The organic layer was washed with 1N sodium hydroxide (250 mL), water (500 mL) and brine (2 × 500 mL), and dried over anhydrous magnesium sulfate. The filtered solution was concentrated and the residue was triturated with hexane to give 37.8 g (84.6%) of the product as an orange solid. Mp 71-73 [deg.] C; MS EI m / e 216 (M ^<+> ). Elemental analysis (as C ₈ H ₉ ClN ₂ O ₃ ): Calculated: C, 44.36; H, 4.19; N, 12.93 Found: C, 44.45; H, 4.02 N, 12.97

Intermediate 4 2- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -6-nito
2-phenylamine 2- (2-chloro-ethoxy) -6 in anhydrous dimethyl sulfoxide (50 mL)
A solution containing -nitro-phenylamine (4.1 g, 19 mmol) and 3- (1H-indol-3-yl) -propylamine (7.1 g, 40.8 mmol) was heated at 60 ° C. for 12 hours. . Ethyl acetate (200 mL) was added and the mixture was saturated with sodium bicarbonate.
Washed with lithium solution (3 × 200 mL) and brine (200 mL). No organic layer
Dry over magnesium sulfate, filter, and concentrate to give the crude product. Chromat
Chromatography (ethyl acetate: hexane: 2N ammonia methanol = 25: 25:
Purification according to 1) gave 4.6 g (68.9%) of the product as a yellowish red viscous oil. MS EI m / e 354 (M⁺). Elemental analysis results (C₁₉H_{twenty two}N_FourO_Three・ 0.4H_TwoO 0.1C_FourH₈O_Two・ 0.05CH _Two Cl_TwoAs): Calculated: C, 62.35; H, 6.38; N, 14.95 Found: C, 62.38; H, 6.30; N, 14.90

Intermediate 5 3- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -benzen-1,2-diamine 2- {2- in ethanol (40 mL) To a solution of [3- (1H-indol-3-yl) -propylamino] -ethoxy} -6-nitro-phenylamine (1.9 g, 5.39 mmol) was added 5% palladium / carbon under nitrogen. (0.5 g) was added. The resulting slurry was hydrogenated at 40 psi for 4 hours. The catalyst was removed by filtration and the ethanol was evaporated to give the crude product. Purification by chromatography (3-10% 2N ammonia methanol in methylene chloride) provided 1.57 g (90.6%) of the product as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ), δ 1.79 (2H, q, J = 7.2 Hz); 2.62 (2H, t, J = 7.1 Hz); 2.71 (2 H, t , J = 7.2 Hz); 2.83 (2H, t, J = 5.2 Hz); 4.09 (2H, br)
4.43 (2H, br); 6.19 (1H, t, J = 8.0 Hz); 6.33 (1H, t, J = 7.9 Hz); 6.94 (1H, t, J = 7.03 (1H, t, J = 7.2Hz); 7.08 (1H, d, J = 2.0Hz); 7.29 (2H, d, J = 7.4Hz) 7.
31 (2H, d, J = 7.4 Hz); 10.7 (1H, br).

Intermediate 6 N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2,2-trifluoro-
N- [3- (1H-Indol-3-yl) -propyl] -acetamide Triethylamine (3.15 mL) in methylene chloride (60 mL) at 60 ° C.
, 22.6 mmol) and 2- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -6-nitro-phenylamine (4.0 g, 11.3 mmol). To the resulting solution, trifluoroacetic anhydride (1.88 mL, 13.3 mmol) was added slowly. The mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (100mL) and saturated sodium bicarbonate solution (100mL). The organic layer was separated, washed with water (100 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. After concentration to give the crude product, purification by chromatography afforded 3.5 g (69.1%) of the product as a viscous reddish orange oil. MS EI m / e 450 (M ⁺ ).

Intermediate 7 N- [2- (2,3-diamino-phenoxy) -ethyl] -2,2,2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -Acetamide N- [2- (2-Amino-3-nitro-phenoxy) -ethyl] -2,2,2-trifluoro-N- [3- (1H-indole under ethanol in ethanol (40 mL) (-3-yl)
To a solution containing -propyl] -acetamide (3.86 g, 8.57 mmol) was added 10% palladium on carbon (1 g). The mixture was hydrogenated at 40 psi for 6 hours. The catalyst was filtered, washed with ethanol, and the filtrate was concentrated to obtain a crude product. Purification by chromatography (40% ethyl acetate-hexane) provided 2.8 g (78.8%) of the product as a viscous brown oil. MS EI m / e 420 (M ^<+> ).

Intermediate 8 2,2,2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -N- [2- (2-oxo-2,3-dihydro-1H -Benzimidazol-4-yloxy) -ethyl] -acetamide N- [2- (2,3-diamino-phenoxy) -ethyl] -2,2,2-trifluoro-N- in anhydrous tetrahydrofuran (50 mL). A mixture of [3- (1H-indol-3-yl) -propyl] -acetamide (0.5 g, 1.19 mmol) and dimidazolecarbonyl (0.39 g, 2.38 mmol) was stirred at 23 ° C. for 5 hours. did. The reaction mixture was poured into water and extracted with ethyl acetate (2x250mL). The organic layer was washed with water (2 × 250 mL) and brine (200 mL) and dried over anhydrous magnesium sulfate. The obtained product was concentrated to obtain a crude product. Purification by chromatography (60% ethyl acetate-hexane) and crystallization from ethyl acetate-hexane gave 0.44 g (82.9%) of the product as a yellowish solid. 180-181 [deg.] C; MS EI m / e 446 (M ^<+> ). Elemental analysis (as _{C 22 H 21 F 3 N 4} O 3): Calculated: C, 59.19; H, 4.74 ; N, 12.55 Found: C, 58.95; H, 4 .82; N, 12.71

Intermediate 9 2,2,2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -N- [2- (2-thioxo-2,3-dihydro-1H -Benzimidazol-4-yloxy) ethyl] -acetamide This compound was prepared as described in Intermediate 8 above, utilizing diimidazolethiocarbonyl, to give the product as a yellow solid. Was. Melting point 12
0-121 <0>C; MS (+) FAB m / e 463 (M + l) ^<+> . Elemental analysis (as _{C 22 H 21 F 3 N 4} O 2 S · 0.33C 4 H 10 O): Calculated: C, 57.40; H, 4.99 ; N, 11.50 Found: C, 57.42; H, 4.93; N, 11.33.

Intermediate 10 2- {2- [3- (5-Fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -6-nitro-phenylamine in anhydrous dimethyl sulfoxide (20 mL) 2- (2-chloro-ethoxy) -6
-Nitro-phenylamine (0.5 g, 2.3 mmol), 3- (5-fluoro-1H-3-
Yl) -propylamine (1.1 g, 5.7 mmol) and triethylamine (0.5
(8 g, 5.7 mmol) was stirred at 90 ° C. for 12 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 ×
(150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride + aqueous ammonia)
) To give 0.67 g (78%) of the product as a yellow oil. MS (EI) 3
58 m / e (M ⁺ ).

Intermediate 11 3- {2- [3- (5-Fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -benzene-1,2-diamine 2- {2 in ethanol -[3- (5-Fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -6-nitro-phenylamine (0.65 g, 1.7 mmol) and a mixture of 10% palladium on carbon Hydrogenated for 3 hours. The catalyst is filtered off,
The solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride
) To give 0.49 g (82%) of the product as a light brown oil. MS (EI) 358 m / e (M ⁺ ).

Intermediate 12 2- (2-chloro-ethoxy) -4-chloro-6-nitro-phenylamine 2- (2-chloro-ethoxy) -6-nitro-phenylamine (30.0 g, 0.14 ), N-chlorosuccinimide and acetonitrile (1.3 L) were refluxed for 4 hours. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500mL). The organic layer was washed with water (2 × 250 mL) and brine (250 mL), dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5 g (95.3%) of the product as an orange solid. 109-110 ° C; MS (EI) 250/252/2
54 m / e (M ⁺ ). Elemental analysis (as _{C 8 H 8 Cl 2 N 2} O 3): Calculated: C, 38.27; H, 3.21 ; N, 11.16 Found: C, 38.15; H, 3 .10; N, 10.96

Intermediate 13 3- {2- [3- (5-Fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -benzene-5-chloro-1,2-diamine in ethanol A mixture of 2- (2-chloro-ethoxy) -4-chloro-6-nitro-phenylamine (0.65 g, 1.7 mmol) and 5% platinum / sulfide carbon was hydrogenated for 1 hour. The catalyst was filtered off and the solvent was removed under vacuum. Chromatography (15% methanol-methylene chloride + aqueous ammonia) gave 0.59 of the product.
g (80%) was obtained as a yellow oil. MS (EI) 376 m / e (M ^<+> ).

Intermediate 14 2,6-Dibromo-4-fluorophenol At room temperature, a solution of 4-fluorophenol (25 g, 0.22 mol) in acetic acid (200 mL) was added under mechanical stirring with bromine. (78 g, 0.49 mol) was slowly added dropwise. After 1 hour, the reaction mixture was poured into ice water (1.5 L) and 100 mL of a saturated aqueous sodium bisulfate solution was added. The solid precipitate was filtered and dried to give 51.8 g (86.0%) of a white solid. ¹ H NMR (CDCl ₃ ) δ 5.69 (1 H, s, OH), 7.25 (2 H, d, J = 7.5 Hz); MS EI m / e 268/270/272 ( M ⁺ ). Elemental analysis results (as C ₆ H ₃ Br ₂ FO): Calculated: C, 26.70; H, 1.12 Found: C, 26.64; H, 1.07

Intermediate 15 1- (2-chloroethoxy) -2,6-dibromo-4-fluorobenzene 2,6-dibromo-4-fluoro-phenol (55 g, 0.20 mol), potassium carbonate
(60 g, 0.43 mol), a mixture of 1-bromo-2-chloroethane (32.5 g, 0.23 mol) and 2-butanone (500 mL) was heated at reflux for 2 hours and cooled to ambient temperature.
Rejected. The solid was filtered and the solvent was removed under vacuum to give an oil. Oil
Dissolve in ethyl ether (300 mL), wash with water, and dry over anhydrous magnesium sulfate.
Dry, treat with charcoal and filter through silica gel to give 65.9 g (97%) of product.
.2%) as an oil. MS EI m / e 330/332/334/336 (M ⁺ );¹H NMR (CDCl_Three) δ 3.89 (2H, t, J = 6.1 Hz), 4.23 (2H,
t, J = 6.1 Hz), 7.28 (2H, d, J = 7.5 Hz).

Intermediate 16 1- (2-Chloroethoxy) -2,6-dibromo-4-fluoro-3-nitrobenzene 1- (2-Chloroethoxy) in concentrated sulfuric acid (165 mL) maintained at room temperature using a water bath. ) -2,6-dibromo-4-fluorobenzene (65.8 g, to a solution of 0.20 mL), was slowly added a solution of nitric acid (H ₂ SO ₄ 10mL HNO ₃ in 165 mL) in sulfuric acid. After stirring the reaction at room temperature for 1 hour, it was poured into ice (1.5 L) and extracted with methylene chloride (2 × 300 mL). The combined organic layers were washed with aqueous sodium bicarbonate (150 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo to give 73.3 g (97.1%) of a white crystalline solid. I got Melting point 56
５７57 ° C .; MS EI m / e 375/377/379/381; ¹ H NMR (CDC
l ₃ ) δ 3.91 (2H, t, J = 5.9 Hz), 4.29 (2H, d, J = 5.9 Hz), 7
.54 (8.1 Hz). Elemental analysis (as C ₈ H ₅ Br ₂ ClFNO ₃ ): Calculated: C, 25.46; H, 1.34; N, 3.71 Found: C, 25.46; H, 1.20 N, 3.51

Intermediate 17 1- (2-Chloroethoxy) -4-fluoro-3-aminobenzene 1% in ethanol (1.1 L) containing 10% palladium / 7.3 g carbon.
(2-Chloroethoxy) -2,6-dibromo-4-fluoro-3-nitrobenzene (73.2
g, 0.19 mol) was hydrogenated at 40 psi for 5 days. The catalyst was filtered and the solvent was removed. The residue was dissolved in diethyl ether (300 mL) and washed with a saturated aqueous sodium carbonate solution (200 mL). The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. Removal of the solvent gave an oil. This solidified to give 32.5 g (90.0%) of the product as a dark solid. Melting point 42-43
° C .; MS EI m / e 189/191 (M ⁺ ); ¹ H NMR (CDCl ₃ ) δ 3.40-3.60 (2H, bs, NH ₂ ), 3.77 (2H, d, J = 6 Hz) , 4.14 (2H, d, J = 6 Hz), 6.19-6.23 (1H, m), 6.36 (1H, dd, J = 7.3 Hz), 6.88 (1H, dd, J = 11.9 Hz). Elemental analysis results (as C ₈ H ₉ ClFNO): Calculated: C, 50.68; H, 4.78; N, 7.39 Found: C, 50.46; H, 4.66; N, 7.46

Intermediate 18 4- (2-chloroethoxy) -7-fluoro-3-thiomethyl-1,3-dihydro-indo
Ethyl (2-methylthio) acetate in anhydrous methylene chloride (200 mL) at -78 ° C.
To a solution of toluene (7.2 g, 53.4 mmol) was added sulfuryl chloride (8.1 g, 59.7 mmol). The mixture was stirred for 20 minutes. 1- (2-chloroethoxy) -4-fluoro-3-aminobenzene (10.0 g, 5 g) in methylene chloride (100 mL)
After stirring a solution of 2.8 mmol) and proton sponge (13.9 g) for 2 h, triethylamine (6.5 g, 64.5 mmol) was added. Keep the temperature at -78 ° C.
And the reaction mixture was stirred for 1 hour. After warming to room temperature, the mixture was poured into brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to give an oil. Acetic acid (75 mL) was added to the oil and the mixture was left for 18 hours
. Then the solvent was removed under vacuum. The residue was treated with diethyl ether (400 mL) and 2
Partitioned with 1.5N aqueous hydrochloric acid (150 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to give a solid. Remove the solids
Trituration with ethyl ether (30 mL) yielded 8.8 g (60.5%) of the product as a yellow
Obtained as a solid. 140-141 ° C; MS EI m / e 275/277 (M ⁺ );¹H NMR (CDCl_Three) δ 2.14 (3H, s), 3.79-3.87 (2H, m), 4.25-4.33 (2H, m), 4.35 (1H, s), 6.51 (1H , dd, J = 9.1
, 3.3 Hz), 6.99 (1H, approximately t, J = 9.1 Hz), 8.09 (1H, s). Elemental analysis results (C₁₁H₁₁ClFNO_TwoAs S): Calculated: C, 47.92; H, 4.02; N, 5.08 Found: C, 47.67; H, 3.85; N, 4.85.

Intermediate 19 7-Fluoro-3-thiomethyl-4- {2- [3- (1H-indol-3-yl) -propyl-amino] -ethyl} -1,3-dihydro-indole-2 -One 4- (2-chloroethoxy) -7- in anhydrous dimethyl sulfoxide (20 mL)
Fluoro-3-thiomethyl-1,3-dihydro-indol-2-one (1.48 g, 5.4 mmol) and 3- (1H-indol-3-yl) -propylamine (3.19 g,
(18.3 mmol) was stirred at 95-105 ° C for 5 hours and at 115 ° C for another 3 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with saturated sodium carbonate (3 × 40 mL) and water (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) provided 1.34 g (52%) of the product as a brown oil.

Example 1 [2- (3H-benzimidazol-4-yloxy) -ethyl]-[3- (1H-indol-3-yl) -propyl] -amine 3 dissolved in 15 mL of formic acid (98%) -{2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -benzene-1,2-diamine (0.75 g, 2.3 mmol)
) Was heated to 104 ° C. for 6 hours. After standing at 25 ° C. overnight, excess formic acid was removed by vacuum distillation. There water (100 mL) and ethyl acetate (100 mL)
Was added. The ethyl acetate layer was separated, washed once with water (50 mL), and once with brine (75 mL) and dried over anhydrous magnesium sulfate. The solvent is concentrated and the product 0.7
g were obtained as a brown solid. Purification by chromatography (2N ammonia in methanol: methylene chloride = 20: 1.5) and crystallization from ethyl acetate-ethanol gave 0.345 g (44.8%) of the product as a white solid. Obtained. 121-124 ° C (decomposition). The HCl salt was prepared in ethanol. 256-258 ° C (decomposition). Elemental analysis (as _{C 20 H 22 N 4 O ·} 2HCl · 0.25H 2 O): Calculated: C, 58.33; H, 6.00 ; N, 13.60 Found: C, 58. 25; H, 5.92; N, 13.38

Example 2 4- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1,3-dihydrobenzimidazol-2-one methanol-tetrahydrofuran (10 mL, 1: 1) and potassium carbonate (1.0 g, 7.4 mmol) in water (3 mL) and 2,2,2-trifluoro-N- [
3- (1H-indol-3-yl) -propyl] -N- [2- (2-oxo-2,3-dihydro-
1H-benzimidazol-4-yloxy) -ethyl] acetimide (0.41 g, 0
(.92 mmol) was heated at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (100mL) and washed with water (80mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give a crude solid product. Crystallization from ethyl acetate-hexane gave 0.25 g (77.7%) of the product as a yellow solid. 130 ° C; MS EI m / e 350 (M ⁺ ). The HCl salt was prepared in ethyl acetate. 222.5-224 ° C. Elemental analysis (as _{C 20 H 22 N 4 O 2} · HCl): Calculated: C, 60.55; H, 6.18 ; N, 13.85 Found: C, 60.75; H, 6 .08; N, 13.69

Example 3 4- {2- [3- (1H-Indol-3-yl) -propylamino] -ethoxy} -1,3-dihydrobenzimidazol-2-thione This compound is 2,2, 2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -N- [2- (2-thioxo-2,3-dihydro-1H-benzo-imidazole-4
Prepared as described in Example 2 by utilizing [-yloxy) ethyl] -acetamide to give the product as a white solid. The HCl salt was prepared in ethyl acetate. Melting point> 260 ° C. Elemental analysis (as _{C 20 H 22 N 4 OS ·} HCl · 0.25H 2 O): Calculated: C, 58.96; H, 5.81 ; N, 13.75 Found: C, 58. 94; H, 5.74; N, 13.51

Example 4 [2- (3H-Benzimidazol-4-yloxy) -ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl] -amine Formic acid (30 mL) A solution of 3- {2- [3- (5-fluoro-1H-indole-3-yl) -propylamino] -ethoxy} -benzene-1,2-diamine (0.49 g) was refluxed for 4 hours. The mixture was poured into sodium hydroxide solution (1N, 150 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-methylene chloride) provided 0.25 g (50%) of the product as an off-white solid. 93-95 ° C. Oxalate was prepared in ethanol. 185-187 ° C. Elemental analysis (as _{C 20 H 21 FN 4 O ·} 2C 2 H 2 O 4): Calculated: C, 54.13; H, 4.73 ; N, 10.52 Found: C, 53.98 H, 4.74; N, 10.49

Example 5 [2- (6-Chloro-1H-benzimidazol-4-yloxy) -ethyl]-[3- (5-
Fluoro-1H-indol-3-yl) -propyl] -amine This compound is 3- {2- [3- (5-fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -benzene- Replacing 1,2-diamine with 3- {2- [3- (5-fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -benzene-5-chloro-1,2-diamine And the product was obtained as a white solid in 76% yield (0.22 g). 96-99 ° C. Oxalate was prepared in ethanol. 185-187 ° C. Elemental analysis (as _{C 20 H 21 FN 4 O ·} 2C 2 H 2 O 4 · 2H 2 O): Calculated: C, 47.81; H, 4.68 ; N, 9.29 Found: C H, 4.26; N, 7.92.

Example 6 7-Fluoro-4- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1,3-dihydro-indol-2-one ethanol (160 mL 7) -fluoro-3-thiomethyl-4- {2- [3- (
A mixture of 1H-indol-3-yl) -propyl-amino] -ethyl} -1,3-dihydro-indole-2-one (1.34 g, 3.5 mmol) and Raney nickel was stirred for 5 hours. The catalyst was filtered off and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) gave 0.24 g (19%) of the product as an oil. MS (EI) 358 m / e (M ^<+> ). Fumarate was prepared in ethanol. Melting point 189-190 [deg.] C. Elemental analysis results (as C ₂₁ H ₂₂ FN ₃ O ₂ · C ₂ H ₂ O ₄ ): Calculated: C, 62.11; H, 5.42; N, 8.69 Found: C, 62. 16; H, 5.45; N, 8.59

The activity of the compounds according to the invention is demonstrated by the following standard pharmacological tests.

PCR cloning of the human 5-HT _1A receptor subtype from a human genomic library has already been reported by Chanda et al. [Molecular.
Pharmacology ( Mol. Pharmacol. ), 43: 516 (1993)]. Through this study, we adopted the human 5-HT _1A receptor stable Chinese hamster ovary fine vesicular systems expressing subtype (5-HT _1A .CHO cells). Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin / streptomycin.

After growing the cells as a monolayer to 95-100% confluence, the membrane was harvested for binding studies. Gently scrape cells from culture plate, transfer to centrifuge tube,
Centrifuge in buffer (50 mM Tris; pH 7.5) (2000 rpm for 10 minutes,
(4 ° C.). The resulting pellet was aliquoted and stored at -80 ° C. On the day of the assay, cells were thawed on ice and resuspended in buffer. [ ³ H] 8-OH
Studies were performed using -DPAT as radioligand. Binding assays were performed in a 96-well microtiter plate with a final total volume of buffer of 250 μL. Competition experiments were performed using seven concentrations of unlabeled drug and a final ligand concentration of 1.5 nM. Non-specific binding was determined in the presence of 10 μM 5-HT. Saturation analysis was performed using [ ³ H] 8-OH-DPAT at concentrations ranging from 0.3 to 30 nM. After incubation at room temperature for 30 minutes, ice-cold buffer was added and the M-96 Brandel cell harvester (Gaithersburg) was added.
), Maryland), the reaction was stopped by rapid filtration through a GF / B filter presoaked in 0.5% polyethyleneimine for 30 minutes.

[0052] Chisamu (Cheetham) that used by al [neuro Pharmacology, 32 (Neu rophamacol.): 737 (1993)] using a similar protocol was measured affinity of a compound for serotonin transformer Porter . Briefly, frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with ³ H-paroxetine (0.1 nM) at 25 ° C. for 60 minutes. All tubes also contained either excipients, test compounds (1-8 concentrations), or saturating concentrations of fluoxetine (10 μM) that defined specific binding. After stopping all reactions by adding ice-cold Tris buffer, the conjugate is separated from free ³ H-paroxetine by rapid filtration using a Tom Tech filter. The radioactivity of the conjugate was measured using Wallac 120
Quantification was performed using a 5 Beta Plate ^R counter. IC ₅₀ values were determined using non-linear regression analysis. This is the case for Cheng and Prusoff
[Biochemical Pharmacol. , 22: 3099 (19
73)]; Ki = IC50 / ((radioligand concentration) / (1 + KD)).

[ ³⁵ S] -GTPγS binding assays were performed using Lazareno and Birdsall (
Birdsall) [British Journal of Pharmacology ( Br. J. Pharmacol. ), 109: 1120 (1993)]. Briefly, membrane fragments of the 5-HT _1A cloned receptor (used in the 5-HT _1A receptor binding assay) were stored at -70 ° C until needed. When needed, the membrane was quickly thawed, centrifuged at 40,000 × g for 10 minutes, and assay buffer (25 mM HEPES, 3 mM MgCl ₂ , 100 mM NaCl, 1 mM EDTA, 10 μM GDP, 500 mM DTT, pH 8). .0) at 4 ° C for 10 minutes. These membranes were then added to [ ³⁵ S] GTPγS (1 nM) in the presence of excipients, test compounds (1-8 concentrations), or an excess of 8-OH-DPAT that defined maximal agonist response.
For 30 minutes at 30 ° C. By adding ice-cold Tris buffer, after all the reaction was stopped, filtered hastily have use a filtration apparatus Tom Tech (Tom Tech ^R), the bound from free ^[35 S] GTPγS separation did. Agonists to increase the amount of binding of ^{[3 5} S] GTPγS, antagonists not increase the binding.
Bound radioactivity was counted and analyzed as described above.

The following assay was performed using 25 mM HEPES, 5 mM theophylline (theo
phylline) and DMEM containing 10 μM pargyline.
Performed by incubating at 20 ° C. for 20 minutes. Functional activity was assayed by treating cells with forskolin (final concentration 1 μM) followed immediately by treatment with test compounds (six concentrations) at 37 ° C. for an additional 10 minutes. In separate experiments, six concentrations of antagonist were pre-incubated for 20 minutes before adding 10 nM 8-OH-DPAT and forskolin. The reaction was stopped by removing the medium and adding 0.5 mL of ice-cold assay buffer. Plates were stored at −20 ° C. before assessing cAMP formation by the cAMP SPA assay (Amersham).

The compounds tested correspond to the compounds prepared in Examples 1 to 6 above. Table 1 shows the results of this method.

[0056]

[Table 1]

As shown by the above results, the compounds of the present invention are active on the 5-HT _1A receptor and generally inhibit serotonin levels by inhibiting 5-HT transport. To rise. Thus, the compounds of the present invention should be useful in treating disorders associated with deficient serotonin levels.

The compounds of the present invention may be administered orally or parenterally, as such, or in combination with conventional pharmaceutical carriers. Applicable solid carriers include one or more of which can also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, flow agent, compression aid, binder, or tablet disintegrant. The above substances or encapsulating materials can be mentioned. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Any solid carrier known to those skilled in the art may be used with the compounds of the present invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose,
Methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of the invention. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. Liquid carriers include other agents such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or osmotic pressure regulators. Can be included. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly as described above with additives such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric alcohols and polyhydric alcohols). Alcohol, for example
Glycols and derivatives thereof, and oils such as fractionated coconut and peanut oils. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used to prepare sterile liquid compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The composition for oral administration may be in the form of a liquid or solid composition.

Preferably, the pharmaceutical compositions containing the compounds of the present invention are in unit dosage form, for example, as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of a compound of the present invention. The unit dosage form can be a packaged composition, for example, packeted powders, vials, ampoules, filled syringes or liquid sachets. Alternatively, the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The therapeutically effective amount and dosage regimen of the compound of the invention administered will include the weight, age, sex and status of the patient, the severity of the disease, the route and frequency of administration, and the particular compound employed. Depends on various factors and can therefore vary widely.
However, it is envisaged that the above pharmaceutical compositions may contain a compound of the present invention in a range of about 0.1 to about 2000 mg, preferably about 0.5 to about 500 mg, more preferably about 1 to about 100 mg. It is. The planned daily dose of the active compound is about 0.01 to about 100 mg / kg body weight. The daily dose can conveniently be administered 2 to 4 times a day.

The present invention may be embodied in other specific forms without departing from its spirit and essential attributes, and thus is intended to indicate the scope of this invention rather than the foregoing specification. Reference should be made to the appended claims.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor James Albert Nelson United States 18977 Pennsylvania Washington Crossing, Decision Way West 7th F term (reference) 4C063 AA01 BB07 CC26 DD06 EE01 4C086 AA01 AA02 AA03 BC13 BC39 GA07 MA01 MA04 NA14 ZA03 ZA12 ZA18 ZC14 4C204 BB01 CB03 GB30 GB01 GB01 GB01

Claims (10)

[Claims] 1. The formula: embedded image Wherein R ₁ is hydrogen, lower alkyl, phenyl or substituted phenyl; X and Y together form a lactam, imidazole, imidazolone or thioimidazolone ring; Z is hydrogen, halogen or lower Alkoxy; W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl group; and n = 2 to 5] or a pharmaceutically acceptable salt thereof. 2. R ₁ is hydrogen; X and Y together form an imidazole or thioimidazolone ring; Z is halogen or hydrogen; W is halogen or hydrogen; and n = 2-3. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, which is [2- (3H-benzimidazol-4-yloxy) -ethyl]-[3- (1H-indol-3-yl) -propyl] -amine. 4. The compound according to claim 1, which is 4- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1,3-dihydrobenzimidazol-2-one. 5. The compound according to claim 1, which is 4- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1,3-dihydrobenzimidazol-2-thione. 6. The compound according to claim 1, which is [2- (3H-benzimidazol-4-yloxy) -ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl] -amine. . 7. [2- (6-Chloro-1H-benzimidazol-4-yloxy)-
The compound according to claim 1, which is ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl] -amine. 8. The method according to claim 1, which is 7-fluoro-4- {2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1,3-dihydro-indol-2-one. The listed compound. 9. The formula: embedded image Wherein R ₁ is hydrogen, lower alkyl, phenyl or substituted phenyl; X and Y together form a lactam, imidazole, imidazolone or thioimidazolone ring; Z is hydrogen, halogen or lower Alkoxy; W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl group; and n = 2 to 5] or a pharmaceutically acceptable salt thereof. 10. A method of alleviating the symptoms of depression in a patient in need thereof, comprising the step of formulating an antidepressant effective amount for said patient: Wherein R ₁ is hydrogen, lower alkyl, phenyl or substituted phenyl; X and Y together form a lactam, imidazole, imidazolone or thioimidazolone ring; Z is hydrogen, halogen or lower An alkoxy; W is a method comprising administering a compound represented by the formula: n is hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl; and n = 2 to 5] or a pharmaceutically acceptable salt thereof.